Compounds of the formula (I), commonly known as “marcolides”, are known in the art:
wherein each vicinal pair of R1 and R2, R3 and R4, R5 and R6 independently may,                a) represent two vicinal hydrogen atoms, or        b) form a second bond between the vicinal carbon atoms to which they are attached; in addition to the meanings above, R2 may represent an alkyl group;        
R7 represents hydrogen, hydroxy group, protected hydroxy or alkyloxy group or, in conjunction with R1, it may represent oxo group;
R8 and R9 independently represent hydrogen or hydroxy group; R10 represents hydrogen, alkyl group, alkyl group substituted by one or more hydroxy groups, alkenyl group, alkenyl group substituted by one or more hydroxy groups, or alkyl group substituted by oxo group;
X represents oxo group, (hydrogen atom, hydroxy group), (hydrogen atom, hydrogen atom) or —CH2O—;
Y represents oxo group, (hydrogen atom, hydroxy group), (hydrogen atom, hydrogen atom) or N—NR11R12 or N—OR13;
R11 and R12 independently represent hydrogen atom, or alkyl, aryl or tosyl group;
R13, R14, R15, R16, R17, R18, R19, R22 and R23 independently represent hydrogen atom or alkyl group;
R20 and R21 independently represent oxo group, or they may independently represent (R20a, hydrogen atom) and (R21a, hydrogen atom) respectively; R20a and R21a independently represent hydroxy group, alkyloxy group, or OCH2OCH2CH2OCH3 or R21a is protected hydroxy group;
in addition R20a and R21a may together represent an oxygen atom in an epoxide ring;
n is 1, 2 or 3;
in addition to the meanings above, Y, R10 and R23, together with the carbon atoms to which they are attached, may represent a 5- or 6-membered N-, S- and/or O-containing heterocyclic ring, which may be saturated or unsaturated, and which may be substituted by one or more groups selected from alkyl group, hydroxy group, alkyl group substituted by one or more hydroxy groups, alkyloxy group, benzyl and —CH2Se(C6H5).
The macrolide compounds represented by formula (I) are known to possess immunosuppressive activity when administered to patients in need thereof. One compound of particular interest is 17-allyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxy-cyclohexyl)-1-methylvinyl)-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone, commonly referred to as tacrolimus or FR-900506 (FK506). Tacrolimus possesses immunosuppressive as well as antimicrobial activity and is therefore useful for the treatment and prevention of rejection of transplantation, graft-vs.-host diseases, auto-immune diseases, infectious diseases and the like.
Compounds according to formula (I), along with their pharmaceutically acceptable salts, are known in the art to be produced by fermentation of Streptomyces tsukubaensis No. 9993 (FERM BP-927) or Streptomyces hygroscopicus subsp. yakushimaensis No. 7238 (FERM BP-928).
Solid dispersions of macrolides, including tacrolimus, are known in the art. Yamashita et al (International Journal of Pharmaceutics, vol. 267, pp. 79-91, (2003)) describes a solid dispersion of tacrolimus in which the entire dosage amount of tacrolimus is formulated by dissolving the tacrolimus in ethanol, adding hydroxyproplymethyl cellulose (HPMC) as a carrier and evaporating the ethanol under vacuum at 40° C.
It is desirable to develop additional solid dispersion formulations of macrolide compounds, such as tacrolimus, which are bioequivalent to FDA approved formulations of those same compounds.